Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD
- 1 June 2007
- journal article
- Published by American Society of Hematology in Blood
- Vol. 109 (11), 5049-5057
- https://doi.org/10.1182/blood-2007-01-067249
Abstract
Antigen-presenting cells (APCs) are critical for the initiation of graft-versus-host disease (GVHD), although the responsible APC subset and molecular mechanisms remain unclear. Because dendritic cells (DCs) are the most potent APCs and the NF-kB/Rel family member RelB is associated with DC maturation and potent APC function, we examined their role in GVHD. Within 4 hours of total body irradiation, RelB nuclear translocation was increased and restricted to CD11chi DCs within the host APC compartment. Furthermore, the transient depletion of CD11chi donor DCs that reconstitute in the second week after transplantation resulted in a transient decrease in GVHD severity. By using RelB−/− bone marrow chimeras as transplant recipients or RelB−/− donor bone marrow, we demonstrate that the induction and maintenance of GVHD is critically dependent on this transcription factor within both host and donor APCs. Critically, RelB within APCs was required for the expansion of donor helper T cell type 1 (Th1) effectors and subsequent alloreactivity, but not the peripheral expansion or function of donor FoxP3+ regulatory T cells. These data suggest that the targeted inhibition of nuclear RelB translocation within APCs represents an attractive therapeutic strategy to dissociate effector and regulatory T-cell function in settings of Th1-mediated tissue injury.Keywords
This publication has 50 references indexed in Scilit:
- Stem cell mobilization with G-CSF analogs: a rational approach to separate GVHD and GVL?Blood, 2006
- Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized graftsNature Immunology, 2006
- Donor APCs are required for maximal GVHD but not for GVLNature Medicine, 2004
- Regulation of secondary lymphoid organ development by the nuclear factor‐κB signal transduction pathwayImmunological Reviews, 2003
- CD40 Ligation Conditions Dendritic Cell Antigen-Presenting Function Through Sustained Activation of NF-κBThe Journal of Immunology, 2002
- Preterminal host dendritic cells in irradiated mice prime CD8+ T cell–mediated acute graft-versus-host diseaseJCI Insight, 2002
- Hyporesponsiveness of Donor Cells to Lipopolysaccharide Stimulation Reduces the Severity of Experimental Idiopathic Pneumonia Syndrome: Potential Role for a Gut-Lung Axis of InflammationThe Journal of Immunology, 2000
- RelB nuclear translocation regulates B cell MHC molecule, CD40 expression, and antigen-presenting cell functionProceedings of the National Academy of Sciences, 2000
- Prevention of Graft Versus Host Disease by Inactivation of Host Antigen-Presenting CellsScience, 1999
- Expression of relB is required for the development of thymic medulla and dendritic cellsNature, 1995